1. Field of the Invention
This invention relates to the use of aryl nitrone compounds as therapeutic agents for the treatment of neuropathic pain in mammals.
2. State of the Art
Neuropathic pain is a category of chronic pain that has been widely studied. Neuropathic pain occurs when the peripheral and/or central nervous systems are sensitized following an injury to the peripheral system. This initial injury can occur from a wide variety of causes including traumatic physical injury, as well as systematic diseases such as diabetes, herpes zoster, AIDS/HIV, syphilis and various other autoimmune diseases.
Examples of pain syndromes of this class include post hepatic neuralgia, neuritis, temporomandibular disorder, myofascial pain, back pain, pain induced by inflammatory conditions. Neuropathic pain may occur in all body regions. Thus, neuropathic pain may e.g., originate from the dental region. Burn injury also often leads to neuropathic hyperalgesia in the affected body area. Neuralgia is characterized, in its acute phase, by intraneural inflammation which can cause damage to primary afferent axons, this inducing neuropathic pain. Neuropathic pain may also be induced by diabetic conditions (diabetic neuropathy). Neuropathy of primary afferent axons in long nerves is found in diabetic patients. Nociceptor sensitization may ensue.
The following more complete listing of pain conditions included within the definition of neuropathic pain may be found in PAIN MANAGEMENT, Rochelle Wagner and Robert R. Myers.
Neuropathic pain conditions are characterized by hyperesthesia (enhanced sensitivity to a natural stimuli), hyperalgesia (abnormal sensitivity to pain), allodynia (widespread tenderness, characterized by hypersensitivity to tactile stimuli) and/or spontaneous burning pain. In humans, neuropathic pains tend to be chronic. Neuropathic pain is generally considered to be nonresponsive or only partially responsive to conventional opioid analgesic regimens. Treatment which work with neuropathic pain are often non-helpful in other pain conditions. Consequently, alternate therapies for the management of neuropathic pain are widely sought.
The present invention provides compositions and methods for treating these forms of neuropathic pain. These compositions and methods employ 3,4,5-trisubstituted arylnitrone compounds as their active agents. Many of the compounds themselves have already been disclosed in commonly-owned U.S. Patent Application Ser. No. 60/110,541 (filed 2 Dec. 1998) and PCT Application WO 0032567 (published 8 Jun. 2000). Other compounds were disclosed in U.S. Pat. No. 5,455,272.
In accord with this invention, pain, particularly neuropathic pain as described above, is treated by administering to a patient suffering from such pain an effective, pain-treating amount of one or more 3,4,5-trisubstituted aryl nitrone compounds.
Accordingly, in one aspect, this invention is directed to administering to a neuropathic pain sufferer one or more compounds of formula I: 
wherein R1 is selected from the group consisting of hydrogen, alkyl 
each R2 is independently selected from a group of the formula: 
R3 is selected from the group consisting of hydrogen, alkyl, cycloalkyl and aryl;
R4 is selected from the group consisting of alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, cycloalkyl, substituted cycloalkyl, cycloalkenyl and substituted cycloalkenyl;
R5 is selected from the group consisting of alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, cycloalkyl, substituted cycloalkyl, cycloalkenyl and substituted cycloalkenyl;
R6 and R7 are independently selected from the group consisting of hydrogen, alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, cycloalkyl, substituted cycloalkyl, cycloalkenyl and substituted cycloalkenyl; or R6 and R7 can be joined to form an alkylene or substituted alkylene group having from 2 to 10 carbon atoms;
R8 is selected from the group consisting of alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, cycloalkyl, substituted cycloalkyl, cycloalkenyl and substituted cycloalkenyl;
R9 is selected from the group consisting of hydrogen, alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, cycloalkyl, substituted cycloalkyl, cycloalkenyl and substituted cycloalkenyl; or R8 and R9 can be joined to form an alkylene or substituted alkylene group having from 2 to 10 carbon atoms;
R10 is selected from the group consisting of hydrogen, lower alkyl and lower cycloalkyl; or R1 and R10 can be joined to form an alkylene, substituted alkylene, xe2x80x94C(O)xe2x80x94 xe2x80x94S(O)xe2x80x94 or xe2x80x94S(O)2xe2x80x94 group;
R11 and R12 are independently selected from the group consisting of lower alkyl and lower cycloalkyl; or R11 and R12 can be joined to form an alkylene group having from 2 to 10 carbon atoms;
X is oxygen, sulfur, xe2x80x94S(O)xe2x80x94 or xe2x80x94S(O)2xe2x80x94; and
W is oxygen or sulfur; and pharmaceutically-acceptable salts thereof.
Preferably, R3 is hydrogen or lower alkyl. More preferably, R3 is hydrogen or alkyl having 1 to 4 carbon atoms, more preferably 1 or 2 carbon atoms. Still more preferably, R3 is hydrogen.
R4 is preferably selected from the group consisting of alkyl, substituted alkyl and cycloalkyl. More preferably, R4 is alkyl having 3 to 6 carbon atoms or cycloalkyl having 5 to 6 carbon atoms. Particularly preferred R4 groups include methyl, n-propyl, isopropyl, 1-hydroxy-2-methylprop-2-yl, n-butyl, tert-butyl, 3-thiomethylpropyl, 3-(thiomethoxy)but-1-yl, cyclohexyl, 4-trifluoromethybenzyl and 3,4,5-trimethoxybenzyl.
R5 is preferably selected from the group consisting of alkyl and cycloalkyl. More preferably, R5 is lower alkyl. Particularly preferred R5 groups include methyl, ethyl, n-propyl, isopropyl and n-butyl.
R6 is preferably selected from the group consisting of alkyl and alkoxycarbonylalkyl (i.e., ROC(O)-alkyl-, where R is alkyl or cycloalkyl). Particularly preferred R6 groups include ethyl, n-propyl, isopropyl, n-butyl, ethoxycarbonylmethyl and 2-(ethoxycarbonyl)ethyl. R7 is preferably hydrogen.
Preferably, R8 is alkyl or alkoxyalkyl (i.e., RO-alkyl-, where R is alkyl). Particularly preferred R8 groups include methyl and methoxyethyl. R9 is preferably hydrogen.
Preferably, X is oxygen.
Preferably, R10, R11 and R12 are independently lower alkyl. More preferably, R10, R11 and R12 are methyl.
W is preferably oxygen.
In one preferred embodiment, this method employs a compound of formula IA: 
wherein R14 is selected from the group consisting of alkyl, substituted alkyl, cycloalkyl and substituted cycloalkyl; and pharmaceutically-acceptable salts thereof and R14 is preferably selected from the group consisting of alkyl, substituted alkyl and cycloalkyl. More preferably, R14 is alkyl having 3 to 8 carbon atoms or cycloalkyl having 5 to 6 carbon atoms. Particularly preferred R14 groups include methyl, n-propyl, isopropyl, 1-hydroxy-2-methylprop-2-yl, n-butyl, tert-butyl, tert-octyl and cyclohexyl.
In another preferred embodiment, this method employs a compound of formula II: 
wherein R13 is selected from the group consisting of alkyl, substituted alkyl, cycloalkyl and substituted cycloalkyl; and R14 is selected from the group consisting of alkyl, substituted alkyl, cycloalkyl and substituted cycloalkyl; and pharmaceutically-acceptable salts thereof.
Preferably, R13 is lower alkyl.
R14 is preferably selected from the group consisting of alkyl, substituted alkyl and cycloalkyl. More preferably, R14 is alkyl having 3 to 6 carbon atoms or cycloalkyl having 5 to 6 carbon atoms. Particularly preferred R14 groups include methyl, n-propyl, isopropyl, 1-hydroxy-2-methylprop-2-yl, n-butyl, tert-butyl, 3-thiomethylpropyl, 3-(thiomethoxy)but-1-yl, cyclohexyl, 4-trifluoromethybenzyl and 3,4,5-trimethoxybenzyl.
In another preferred embodiment, this invention employs a compound of formula III to treat pain: 
wherein R15 and R16 are independently selected from the group consisting of hydrogen, alkyl, substituted alkyl, cycloalkyl, substituted cycloalkyl; or R15 and R16 can be joined to form an alkylene or substituted alkylene group having from 2 to 10 carbon atoms;
R17 is selected from the group consisting of alkyl, substituted alkyl, cycloalkyl and substituted cycloalkyl; and pharmaceutically-acceptable salts thereof.
R15 is preferably selected from the group consisting of alkyl and alkoxycarbonylalkyl (i.e., ROC(O)-alkyl-, where R is alkyl or cycloalkyl). Particularly preferred R15 groups include ethyl, n-propyl, isopropyl, n-butyl, ethoxycarbonylmethyl and 2-(ethoxycarbonyl)ethyl. R16 is preferably hydrogen.
R17 is preferably selected from the group consisting of alkyl, substituted alkyl and cycloalkyl. More preferably, R17 is alkyl having 3 to 6 carbon atoms or cycloalkyl having 5 to 6 carbon atoms. Particularly preferred R17 groups include methyl, n-propyl, isopropyl, 1-hydroxy-2-methylprop-2-yl, n-butyl, tert-butyl, 3-thiomethylpropyl, 3-(thiomethoxy)but-1-yl, cyclohexyl, 4-trifluoromethybenzyl and 3,4,5-trimethoxybenzyl.
In still another preferred embodiment, this invention is directed to the use of a compound of formula IV to treat pain: 
wherein R18 is selected from the group consisting of alkyl, substituted alkyl, cycloalkyl and substituted cycloalkyl;
R19 is selected from the group consisting of hydrogen, alkyl, substituted alkyl, cycloalkyl and substituted cycloalkyl; or R18 and R19 can be joined to form an alkylene or substituted alkylene group having from 2 to 10 carbon atoms;
R20 is selected from the group consisting of alkyl, substituted alkyl, cycloalkyl and substituted cycloalkyl; and pharmaceutically-acceptable salts thereof.
Preferably, R18 is alkyl or alkoxyalkyl (i.e., RO-alkyl-, where R is alkyl). Particularly preferred R18 groups include methyl and methoxyethyl. R19 is preferably hydrogen.
Particularly preferred 3,4,5-trisubstituted aryl nitrone compounds for use in the invention include those having the formulae shown in Tables I, II, III and IV.
Accordingly, in another of its composition aspects, this invention is directed to the use of each of the following individual compounds to treat pain:
xcex1-(4-acetoxy-3,5-di-tert-butylphenyl)-N-tert-butylnitrone
xcex1-(4-isobutanoyloxy-3,5-di-tert-butylphenyl)-N-tert-butylnitrone
xcex1-(4-n-butanoyloxy-3,5-di-tert-butylphenyl)-N-tert-butylnitrone
xcex1-(4-acetoxy-3,5-di-tert-butylphenyl)-N-isopropylnitrone
xcex1-(4-acetoxy-3,5-di-tert-butylphenyl)-N-1-hydroxy-2-methylprop-2-ylnitrone
xcex1-(4-n-pentanoyloxy-3,5-di-tert-butylphenyl)-N-tert-butylnitrone
xcex1-(4-acetoxy-3,5-di-tert-butylphenyl)-N-4-trifluoromethylbenzylnitrone
xcex1-(4-propionyloxy-3,5-di-tert-butylphenyl)-N-tert-butylnitrone
xcex1-(4-acetoxy-3,5-di-tert-butylphenyl)-N-methylnitrone
xcex1-(4-acetoxy-3,5-di-tert-butylphenyl)-N-3,4,5-trimethoxybenzylnitrone
xcex1-[4-(ethylaminocarbonyloxy)-3,5-di-tert-butylphenyl]-N-tert-butylnitrone
xcex1-[4-(n-propylaminocarbonyloxy)-3,5-di-tert-butylphenyl]-N-tert-butylnitrone
xcex1-[4-(n-butylaminocarbonyloxy)-3,5-di-tert-butylphenyl]-N-tert-butylnitrone
xcex1-[4-(2-ethoxycarbonyl)ethylaminocarbonyloxy)-3,5-di-tert-butylphenyl]-N-tert-butylnitrone
xcex1-[4-(2-ethoxycarbonyl)methylaminocarbonyloxy)-3,5-di-tert-butylphenyl]-N-tert-butylnitrone
xcex1-(4-methoxymethoxy-3,5-di-tert-butylphenyl)-N-tert-butylnitrone
xcex1-[4-(2-methoxy)ethoxymethoxy-3,5-di-tert-butylphenyl]-N-tert-butylnitrone
xcex1-(4-methoxymethoxy-3,5-di-tert-butylphenyl)-N-3-(thiomethoxy)but-1-ylnitrone
xcex1-(4-hydroxy-3,5-di-tert-butylphenyl)-N-tert-butylnitrone
xcex1-(4-hydroxy-3,5-di-tert-butylphenyl)-N-tert-octylnitrone
xcex1-(4-methoxymethoxy-3,5-di-tert-butylphenyl)-N-3-thiomethoxypropylnitrone
a-(4-hydroxy-3,5-dimethoxyphenyl)-N-tert-butylnitrone (m.p. 185.4xc2x0 C.)
a-(4-hydroxy-3,5-dimethylphenyl)-N-hexylnitrone (m.p. 128xc2x0 C.)
a-(4-hydroxy-3,5-dimethylphenyl)-N-tert-butylnitrone (m.p. 197.5-198.3xc2x0 C.)
a-(4-hydroxy-3,5-di-tert-butylphenyl)-N-(1,1-dimethyl-2-hydroxyethyl)nitrone (m.p. 185-191xc2x0 C.)
a-(4-hydroxy-3,5-di-tert-butylphenyl)-N-(1,1-dimethylpropyl)nitrone (m.p. 215xc2x0 C.)
a-(4-hydroxy-3,5-di-tert-butylphenyl)-N-(1-methylethyl)nitrone (m.p. 176xc2x0 C.)
a-(4-hydroxy-3,5-di-tert-butylphenyl)-N-benzylnitrone (m.p. 123.3xc2x0 C.)
xcex1-(4-methoxymethoxy-3,5-di-tert-butylphenyl)-N-cyclohexylmethylnitrone
xcex1-(4-methoxymethoxy-3,5-di-tert-butylphenyl)-N-(2-tetrahydrofuryl) nitrone
xcex1-(4-methoxymethoxy-3,5-di-tert-butylphenyl)-N-benzylnitrone
xcex1-(4-methoxy-3,5-di-tert-butylphenyl)-N-tert-butylnitrone
xcex1-(4-ethoxy-3,5-di-tert-butylphenyl)-N-tert-butylnitrone
xcex1-(4-carbethoxymethoxy-3,5-di-tert-butylphenyl)-N-tert-butylnitrone
and pharmaceutically acceptable salts thereof.
In composition aspects, this invention is directed to pharmaceutical compositions comprising a pharmaceutically acceptable carrier and an effective neuropathic pain-treating amount of a compound of formula I, II, III or IV above.